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STAT3 selectively interacts with Smad3 to antagonize TGF-β

Oncogene volume 35, pages 4388–4398 (2016)Cite this article

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An Erratum to this article was published on 27 June 2016

Abstract

Smad and STAT proteins are critical signal transducers and transcription factors in controlling cell growth and tumorigenesis. Here we report that the STAT3 signaling pathway attenuates transforming growth factor-β (TGF-β)-induced responses through a direct Smad3–STAT3 interplay. Activated STAT3 blunts TGF-β-mediated signaling. Depletion of STAT3 promotes TGF-β-mediated transcriptional and physiological responses, including cell cycle arrest, apoptosis and epithelial-to-mesenchymal transition. STAT3 directly interacts with Smad3 in vivo and in vitro, resulting in attenuation of the Smad3–Smad4 complex formation and suppression of DNA-binding ability of Smad3. The N-terminal region of DNA-binding domain of STAT3 is responsible for the STAT3–Smad3 interaction and also indispensable for STAT3-mediated inhibition of TGF-β signaling. Thus, our finding illustrates a direct crosstalk between the STAT3 and Smad3 signaling pathways that may contribute to tumor development and inflammation.

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Acknowledgements

We thank David Luskutoff for p800 (PAI-1)-luc, Peter ten Dijke for CAGA-luc, Bert Vogelstein for WWP1 (p21)-luc and SBE-luc and Xiao-Fan Wang for p15-luc. We are grateful to colleagues in our laboratories for helpful discussion and technical assistance. This research was partly supported by grants from MOST (2012CB966600) and NSFC (31571447; 31090360), NIH (R01GM63773, R01 AR053591, R01CA108454 and R01DK073932), Project 111, Project 985 and the Fundamental Research Funds for the Central Universities.

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Author notes

  1. C Sun

    Present address: 7Current address: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.,

Authors and Affiliations

  1. Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China

    G Wang, Y Yu, T Liu & X-H Feng

  2. Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA

    G Wang, X Lin & X-H Feng

  3. Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA

    C Sun & X-H Feng

  4. Department of Hepatobiliary and Pancreatic Surgery and the Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, School of Medicine Zhejiang University, Hangzhou, Zhejiang, China

    T Liang

  5. Institute of Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    L Zhan

  6. Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    X-H Feng

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Correspondence to X-H Feng.

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Wang, G., Yu, Y., Sun, C. et al. STAT3 selectively interacts with Smad3 to antagonize TGF-β. Oncogene 35, 4388–4398 (2016). https://doi.org/10.1038/onc.2015.446

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